1,8-Dihydroxy-9-anthrones derivatives substituted in the 10-position by an unsaturated radical used in human medicine

ABSTRACT

1,8-dihydroxy-9-anthrone derivatives, substituted in the 10-position by an unsaturated radical, are described which have utility as ingredients in human and veterinary pharmaceutical and cosmetic preparations and which are compounds of the structural formula ##STR1## wherein R 1  represents a hydrogen atom or a --CO 2  R&#39; 2  radical, 
     R 2  and R&#39; 2  identical or different, represent a hydrogen atom, a linear or branched chain alkyl radical having 1 to 6 carbon atoms, a cycloalkyl radical having 4 to 6 carbon atoms or a benzyl radical, 
     or R 1  and R 2  taken together form a radical --CO--, and 
     n is 0 or 1, 
     with the proviso that when n is 0 and R 1  is --CO 2  R&#39; 2 , R 2  and R&#39; 2  do not simultaneously represent the radical CH 3 , 
     and the isomers of the compounds of formula (I) and mixtures thereof.

This application is a divisional application of Ser. No. 346,893, filedFeb. 8, 1982, now U.S. Pat. No. 4,464,301.

The present invention relates to novel derivatives of novel1,8-dihydroxy-9-anthrones substituted in the 10-position by anunsaturated radical and their utilization in human and veterinarymedicine and particularly in the treatment of psoriasis as well as incosmetic.

These 1,8-dihydroxy-9-anthrones substituted in the 10-position by anunsaturated radical may be represented as compounds of the generalformula: ##STR2## wherein: R₁ represents a hydrogen atom or a --CO₂ R'₂radical,

R₂ and R'₂, identical or different, represent a hydrogen atom, a linearor branched chain alkyl radical having 1 to 6 carbon atoms, a cycloalkylradical having 4 to 6 carbon atoms or a benzyl radical,

or R₁ and R₂ taken together form a radical --CO--, and

n is 0 or 1,

with the proviso that when n is 0 and R₁ is --CO₂ R'₂, R₂ and R'₂ do notsimultaneously represent the radical CH₃,

and the isomers of the compounds of formula (I) and mixtures thereof,

Among the linear or branched chain alkyl radicals having 1 to 6 carbonatoms within the definition of R₂ and R'₂ the following radicals can becited: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiarybutyl, pentyl, and hexyl.

Among the cycloalkyl radicals within the definition of R₂ and R'₂ thefollowing can be cited: cyclobutyl, cyclopentyl, and cyclohexyl.

According to a first object, the compounds according to the inventionhave the general formula: ##STR3## wherein R₂ represents a hydrogenatom, a linear or branched chain alkyl radical having 1 to 6 carbonatoms, a cycloalkyl radical having 4 to 6 carbon atoms or a benzylradical, and

n is 0 or 1.

According to a second object, the compounds of the invention have thegeneral formula: ##STR4## wherein R'₂ represents a hydrogen atom, alinear or branched chain alkyl radical having 1 to 6 carbon atoms, acycloalkyl radical having 4 to 6 carbon atoms, or a benzyl radical,

R"₂ represents a hydrogen atom, a linear or branched chain alkyl radicalhaving 2 to 6 carbon atoms, a cycloalkyl radical having 4 to 6 carbonatoms, or a benzyl radical, and

n is 0 or 1.

According to the general formula (I), the compounds of the invention canbe represented by the two following formulas (II) or (III) or in theform of their mixture. ##STR5## In these formulas the radicals R₁ and R₂have the same meaning as above.

Some methods of preparation which are described herein below aresusceptible of directing formation of a compound of structure (II) or ofa compound of structure (III).

Other methods of synthesis lead to the preponderant formation of acompound (II) or (III) contaminated by one or the other of the isomers.

Purification methods are susceptible in that latter case to isolate oneor the other compound in the pure state.

Among the compounds of the formula (II) there can in particular be citedthose given in Table A.

                                      TABLE A                                     __________________________________________________________________________    Compound No.                R.sub.1  R.sub.2                                  __________________________________________________________________________    1 10-(1,8-dihydroxy-9-anthrone)-yl maleic anhydride                                                       --CO--                                            2 10-(1,8-dihydroxy-9-anthrone)-yl maleic acid                                                            --COOH   H                                        3 diethyl 10-(1,8-dihydroxy-9-anthrone)-yl maleate                                                        --COOC.sub.2 H.sub.5                                                                   --C.sub.2 H.sub.5                        4 dipropyl 10-(1,8-dihydroxy-9-anthrone)-yl maleate                                                       --COOC.sub.3 H.sub.7                                                                   --C.sub.3 H.sub.7                        5 diisopropyl 10-(1,8-dihydroxy-9-anthrone)-yl maleate                                                    --COO--isoC.sub.3 H.sub.7                         isoC.sub.3 H.sub.7                                                            6 dibutyl 10-(1,8-dihydroxy-9-anthrone)-yl maleate                                                        --COOC.sub.4 H.sub.9                                                                   --C.sub.4 H.sub.9                        7 dipentyl 10-(1,8-dihydroxy-9-anthrone)-yl maleate                                                       --COOC.sub.5 H.sub.11                                                                  --C.sub.2 H.sub.11                       8 dihexyl 10-(1,8-dihydroxy-9-anthrone)-yl maleate                                                        --COOC.sub.6 H.sub.13                                                                  --C.sub.6 H.sub.13                       9 dicyclobutyl 10-(1,8-dihydroxy-9-anthrone)-yl maleate                                                   --COOC.sub.4 H.sub.7                                                                   --C.sub.7 H.sub.7                        10                                                                              dicyclopentyl 10-(1,8-dihydroxy-9-anthrone)-yl maleate                                                  --COOC.sub.5 H.sub.9                                                                   --C.sub.5 H.sub.9                        11                                                                              dicyclohexyl 10-(1,8-dihydroxy-9-anthrone)-yl maleate                                                   --COOC.sub.6 H.sub.11                                                                  --C.sub.6 H.sub.11                       12                                                                              dibenzyl 10-(1,8-dihydroxy-9-anthrone)-yl maleate                                                       --COOCH.sub.2 C.sub.6 H.sub.5                                                          --CH.sub.2 C.sub.6 H.sub.5               13                                                                              methyl pentyl 10-(1,8-dihydroxy-9-anthrone)-yl maleate                                                  --COOCH.sub.3                                                                          --C.sub.5 H.sub.11                       14                                                                              methyl hexyl 10-(1,8-dihydroxy-9-anthrone)-yl maleate                                                   --COOCH.sub.3                                                                          -- C.sub.6 H.sub.13                      15                                                                              ethyl butyl 10-(1,8-dihydroxy-9-anthrone)-yl maleate                                                    --COOC.sub.2 H.sub.5                                                                   --C.sub.4 H.sub.9                        16                                                                              ethyl pentyl 10-(1,8-dihydroxy-9-anthrone)-yl maleate                                                   --COOC.sub.2 H.sub.5                                                                   --C.sub.5 H.sub.11                       17                                                                              ethyl hyexyl 10-(1,8-dihydroxy-9-anthrone)-yl maleate                                                   --COOC.sub.2 H.sub.5                                                                   --C.sub.6 H.sub.13                       18                                                                              propyl pentyl 10-(1,8-dihydroxy-9-anthrone)-yl maleate                                                  --COOC.sub.3 H.sub.7                                                                   --C.sub.5 H.sub.11                       19                                                                              isopropyl butyl 10-(1,8-dihydroxy-9-anthrone)-yl                                                        --COO--isoC.sub.3 H.sub.7                                                              --C.sub.4 H.sub.9                          maleate                                                                     20                                                                              methyl 10-(1,8-dihydroxy-9-anthrone)-yl maleate                                                         --COOH   --CH.sub.3                               21                                                                              ethyl 10-(1,8-dihydroxy-9-anthrone)-yl maleate                                                          --COOH   --C.sub.2 H.sub.5                        22                                                                              propyl 10-(1,8-dihydroxy-9-anthrone)-yl maleate                                                         --COOH   --C.sub.3 H.sub.7                        23                                                                              butyl 10-(1,8-dihydroxy-9-anthrone)-yl maleate                                                          --COOH   --C.sub.4 H.sub.9                        24                                                                              pentyl 10-(1,8-dihydroxy-9-anthrone)-yl maleate                                                         --COOH   --C.sub.5 H.sub.11                       25                                                                              hexyl 10-(1,8-dihydroxy-9-anthrone)-yl maleate                                                          --COOH   --C.sub.6 H.sub.13                       __________________________________________________________________________

Among the compounds of formula (III) there can in particular be citedthose given in Table B.

                                      TABLE B                                     __________________________________________________________________________    Compound No.             R.sub.1  R.sub.2                                     __________________________________________________________________________    26                                                                              3-[(1,8-dihydroxy-9-anthron)-10-ylidene]                                                             H        H                                             propionic acid                                                              27                                                                              methyl 3-[(1,8-dihydroxy-9-anthron)-10-ylidene]                                                      H        --CH.sub.3                                    propionate                                                                  28                                                                              ethyl 3-[(1,8-dihydroxy-9-anthron)-10-ylidene]                                                       H        --C.sub.2 H.sub.5                             propionate                                                                  29                                                                              propyl 3-[(1,8-dihydroxy-9-anthron)-10-ylidene]                                                      H        --C.sub.3 H.sub.7                             propionate                                                                  30                                                                              butyl 3-[(1,8-dihydroxy-9-anthron)-10-ylidene]                                                       H        --C.sub.4 H.sub.9                             propionate                                                                  31                                                                              pentyl 3-[(1,8-dihydroxy-9-anthron)-10-ylidene]                                                      H        --C.sub.5 H.sub.11                            propionate                                                                  32                                                                              hexyl 3-[(1,8-dihydroxy-9-anthron)-10-ylidene]                                                       H        --C.sub.6 H.sub.13                            propionate                                                                  33                                                                              cyclobutyl 3-[(1,8-dihydroxy-9-anthron)-10-                                                          H        --C.sub.4 H.sub.7                             ylidene]-propionate                                                         34                                                                              cyclopentyl 3-[(1,8-dihydroxy-9-anthron)-10-                                                         H        --C.sub.5 H.sub.9                             ylidene]-propionate                                                         35                                                                              cyclohexyl 3-[(1,8-dihydroxy-9-anthron)-10-                                                          H        --C.sub.6 H.sub.11                            ylidene]-propionate                                                         36                                                                              3-[(1,8-dihydroxy-9-anthron)-10-                                                                     --COOH   H                                             ylidene]-succinic acid                                                      37                                                                              dimethyl 3-[(1,8-dihydroxy-9-anthron)-10-                                                            --COOCH.sub.3                                                                          --CH.sub.3                                    ylidene]-succinate                                                          38                                                                              diethyl 3-[(1,8-dihydroxy-9-anthron)-10-                                                             --COOC.sub.2 H.sub.5                                                                   --C.sub.2 H.sub.5                             ylidene]-succinate                                                          39                                                                              dipropyl 3-[(1,8-dihydroxy-9-anthron)-10-                                                            --COOCC.sub.3 H.sub.7                                                                  --C.sub.3 H.sub.7                             ylidene]-succinate                                                          40                                                                              diisopropyl 3-[(1,8-dihydroxy-9-anthron)-10-                                                         --COO--isoC.sub.3 H.sub.7                            isoC.sub.3 H.sub.7                                                              ylidene]-succinate                                                          41                                                                              dibutyl 3-[(1,8-dihydroxy-9-anthron)-10-                                                             --COOC.sub.4 H.sub.9                                                                   --C.sub.4 H.sub.9                             ylidene]-succinate                                                          42                                                                              diisobutyl 3-[(1,8-dihydroxy-9-anthron)-10-                                                          --COO--isoC.sub.4 H.sub.9                            isoC.sub.4 H.sub.9                                                              ylidene]-succinate                                                          43                                                                              dipentyl 3-[(1,8-dihydroxy-9-anthron)-10-                                                            --COOC.sub.5 H.sub.11                                                                  --C.sub.5 H.sub.11                            ylidene]-succinate                                                          44                                                                              dihexyl 3-[(1,8-dihydroxy-9-anthron)-10-                                                             --COOC.sub.6 H.sub.13                                                                  --C.sub.6 H.sub.13                            ylidene]-succinate                                                          45                                                                              dicyclobutyl 3-[(1,8-dihydroxy-9-anthron)-10-                                                        --COOC.sub.4 H.sub.7                                                                   --C.sub.4 H.sub.7                             ylidene]-succinate                                                          46                                                                              dicyclopentyl 3-[(1,8-dihydroxy-9-anthron)-10-                                                       --COOC.sub.5 H.sub.9                                                                   --C.sub.5 H.sub.9                             ylidene]-succinate                                                          47                                                                              dicyclohexyl 3-[(1,8-dihydroxy-9-anthron)-10-                                                        --COOC.sub.6 H.sub.11                                                                  --C.sub.6 H.sub.11                            ylidene]-succinate                                                          48                                                                              3-[(1,8-dihydroxy-9-anthron)-10-ylidene]-3-                                                          --COOCH.sub.3                                                                          H                                             methoxycarbonyl propionic acid                                              49                                                                              3-[(1,8-dihydroxy-9-anthron)-10-ylidene]-3-                                                          --COOC.sub.2 H.sub.5                                                                   H                                             ethoxycarbonyl propionic acid                                               50                                                                              3-[(1,8-dihydroxy-9-anthron)-10-ylidene]-3-                                                          --COOC.sub.3 H.sub.7                                                                   H                                             propyloxycarbonyl propionic acid                                            51                                                                              3-[(1,8-dihydroxy-9-anthron)-10-ylidene]-3-                                                          --COOC.sub.4 H.sub.9                                                                   H                                             butyloxycarbonyl propionic acid                                             52                                                                              3-[(1,8-dihydroxy-9-anthron)-10-ylidene]-3-                                                          --COOC.sub.5 H.sub.11                                                                  H                                             pentyloxy propionic acid                                                    53                                                                              3-[(1,8-dihydroxy-9-anthron)-10-ylidene]-3-                                                          --COOC.sub.6 H.sub.13                                                                  H                                             hexyloxycarbonyl propionic acid.                                            __________________________________________________________________________

The compounds according to the invention can be prepared according to afirst synthetic method by condensing an unsaturated ethylenic oracetylenic reagent with 1,8-dihydroxy-9-anthrone (anthralin).

This synthetic method may be represented by the following reactionscheme: ##STR6##

If the compound of formula (2) is an alkyl propriolate (R₁ ═H) thereaction is more particularly orientated to the formation of a compoundof formula (III). By contrast, if the compound of formula (2) is analkyl acetylene dicarboxylate (R₁ ═CO₂ R'₂), the reaction is moreespecially oriented to the formation of a compound of formula (II).

The reaction in presence of the acetylenic compounds (2) is generallyconducted in an organic solvent medium such as dimethylformamide,pyridine or chloroform.

If chloroform is used as a solvent, the reaction is carried out inpresence of a basic catalyst, preferably in presence of4-dimethylaminopyridine.

The reaction is preferably carried out in an inert atmosphere andprotected from atmospheric moisture and from light. The reactiontemperature depends on the nature of the solvent used; thus the reactionis carried out at 0° C. with pyridine, but at room temperature withdimethylformamide and at reflux with chloroform.

The reaction progress is followed by thin layer chromotography in orderto determine the progressive disappearance of 1,8-dihydroxy-9-anthrone.

The reaction time may be varied between several minutes to several hoursin the case of chloroform.

At the end of the reaction, the product is isolated either byprecipitation with a co-solvent or by usual treatment, i.e. by washingthe organic phase and then by concentrating it. The mixture obtained isthen fractionated by column chromotagraphy on silica gel.

The compounds according to the invention may also be obtained byreacting an halogenated ethylenic derivative and more particularly acompound of the formula (3) with 1,8-dihydrox-9-anthrone under the sameconditions which have been described above for the acetylenic reagents.

This method of synthesis leads especially to the compounds of formula(II).

The compounds of formula (II) are, according to this invention,preferably obtained by thermolysis of adducts of1,8-dihydroxy-9-anthrones described in our copending application Ser.No. 312,640 filed Oct. 19, 1981. This method of synthesis can berepresented by the following reaction scheme: ##STR7##

This method of synthesis involves preparing a suspension of an adduct offormula (4) wherein the radical R₁ represents preferably the radical--CO₂ R'₂, i.e. a dialkyl9,10-dihydro-1,8,9-trihydroxy-9,10-anthracene-α,β-endomaleate, in asolvent of high boiling point such as for instance ortho-dichlorobenzeneor decalin.

The mixture obtained is maintained under an inert atmosphere andprotected from light at the boiling point of the solvent for severalhours.

After cooling the reaction mixture, the unreacted starting material isremoved by filtration and the product obtained is isolated either byprecipitation with an appropriate solvent or by column chromatography onsilica gel.

The adducts of formula (4) are prepared by reacting, in an inertatmosphere and protected from light and moisture,1,8-dihydroxy-9-anthrone in an appropriate organic solvent such astetrahydrofuran with an alkyl acetylenedicarboxylate. The presence of acatalyst can be desirable.

The compounds of formula (III), in which R₂ and R'₂ are different, aregenerally obtained by a transesterification reaction by treating thecompounds wherein R₂ =R'₂ with an alcohol in acidic medium.

The object of the present invention is likewise the utilization of thecompounds according to the invention in human or veterinary medicine andparticularly for the treatment of psoriasis or acne, as well as incosmetic.

According to the invention the compounds as defined hereinabove areincorporated into pharmaceutical or cosmetic compositions in aconcentration generally comprised between 0.01 to 5% and preferablybetween 0.1 and 3% in an appropriate pharmaceutical or cosmetic vehicle.

Cutaneous psoriasis is essentially manifested by the appearance of dry,whitish or nacreous scales, especially on the knees, elbows, sacrum,soles of the feet, palms of the hand, chest and face and likewise onhairy hide.

The various tests conducted have shown that the compounds according tothe invention have a good activity when they are incorporated in variouspharmaceutical vehicles for systemic and particularly percutaneous routeof administration.

Several examples will now be given, by way of illustration and withoutany limitative character, of the preparation of the compounds accordingto the invention.

EXAMPLE 1 10-(1,8-dihydroxy-9-anthronyl)maleic anhydride (No. 1)

In a first step 15 g of anthralin are dissolved at 80° C. in 50 ml ofdimethylformamide, freshly distilled, under an argon atmosphere andprotected from light. After return to room temperature a slight excessof bromomaleic anhydride, (7 ml) is added in one batch under stirring.

After two hours all of the anthralin has been transformed; 200 ml ofdichloromethane is then added and the mixture thus obtained is washedrepeatedly with water. The organic layer is dried over sodium sulfate,then evaporated to dryness at reduced pressure.

The solid obtained is washed with ether, then dissolved in methylenechloride and treated with animal charcoal.

The anhydride obtained is finally recrystallized in methylene chloride;the yellow orange crystals have a melting point of 215° C.

Analysis: C₁₈ H₁₀ O₆. Calc: C: 67.09; H: 3.13; O: 29.79. Found: C:67.29; H: 3.41; O: 29.60.

EXAMPLE 2 10-(1,8-dihydroxy-9-anthrone)-yl maleic acid (No. 2)

A solution of 2 g of 10-(1,8-dihydroxy-9-anthrony)maleic anhydride,obtained according to Example 1, in a mixture of 85 ml of acetic acidand 15 ml of water is maintained at reflux for one hour in an inertatmosphere and protected from light. The solution is then evaporated atreduced pressure.

The solid thus obtained is stirred for one hour in 50 ml of methylenechloride, then filtered and dried. 10-(1,8-dihydroxy-9-anthrone)-ylmaleic acid is thus obtained in the form of a yellow orange powderhaving a melting point of 240° C.

Analysis: C₁₈ H₁₂ O₇. Calc: C: 63.53; H: 3.55; O: 32.91. Found: C:63.45; H: 3.71; O: 33.11.

EXAMPLE 3 Diethyl 10-(1,8-dihydroxy-9-anthrone)-yl maleate (No. 3)

To a stirred suspension of 5 g of anthralin in 250 ml of chloroform, inan inert atmosphere, and protected from moisture and light, 5.63 g ofethyl acetylenedicarboxylate and then 300 mg of 4-dimethylaminopyridineare added. The mixture is maintained at the boiling point of chloroformduring 90 minutes after which time all the anthralin has reacted. Thesolvent is then evaporated under reduced pressure and the residue istaken up in a minimum amount of benzene. The benzene phase is thendeposited on a silica gel chromatography column. The desired product iseluted with benzene and then, after concentration of the elution phases,the residue is recrystalized from ethanol.

The yellow crystals thus obtained have a melting point of 122° C.

Analysis: C₂₂ H₂₀ O₇. Calc: C: 66.66; H: 5.08; O: 28.25. Found: C:66.83; H: 5.14; O: 28.20.

EXAMPLE 4 Diisopropyl 10-(1,8-dihydroxy-9-anthrone)-yl maleate (No. 5)

(1) To a suspension of 11.3 g of anthralin in 150 ml of anhydrous THF,placed under an inert atmosphere and protected from atmospheric moistureand light, there are added 15 g of diisopropyl acetylenedicarboxylate,then 4 ml of an 0.5% methanol solution of lithium methylate. Thereaction mixture is brought to the boiling point of THF during twohours, then concentrated under reduced pressure. The dark red residue isdissolved in a minimum amount of toluene. The toluene phase is depositedon a silica gel chromatography column.

The diisopropyl9,10-dihydro-1,8,9-trihydroxy-9,10-anthracene-α,β-endomaleate is elutedwith chloroform, then recrystallized form a methylene chloride/hexanemixture after concentration of the elution phases. After draining anddrying, there are obtained 10 g of white crystals with melting point203° C.

Analysis: C₂₄ H₂₄ O₇. Calc: C: 67.91; H: 5.70; O: 26.39. Found: C:68.15; H: 5.90; O: 26.47.

(2) A solution of 4 g of diisopropyl9,10-dihydro-1,8,9-trihydroxy-9,10-anthracene-α,β-endomaleate in 15 mlof ortho-dichlorobenzene, stirred under an argon atmosphere andprotected from light, is brought at reflux temperature for 40 hours. Thereaction mixture is then filtered. To the filtrate 100 ml of hexane isadded and the resulting precipitate is filtered and dried.

The product obtained is then dissolved in the minimum amount of tolueneand deposited on a silica gel chromatography column. The expectedproduct is eluted with toluene. After concentration of the eluates, therecrystalization from a mixture of hexane and methylene chloride (9:1)gives rise to yellow needles having a melting point of 132° C.

Analysis: C₁₄ H₂₄ O₇. Calc: C: 67.91; H: 5.70; O: 26.39. Found: C:68.01; H: 5.66; O: 26.36.

EXAMPLE 5 Dibutyl 10-(1,8-dihydroxy-9-anthrone)-yl maleate (No. 6)

(1) To a suspension of 3.40 g of anthralin in 40 ml of anhydroustetrahydrofuran, placed under an argon atmosphere and protected fromatmospheric moisture and light, there are successively added 1 ml of a0.5% methanolic solution of lithium methylate, then 5 g of freshlydistilled dibutyl acetylenedicarboxylate. The reaction mixture is thenbrought to the boiling point of tetrahydrofuran during two hours. It isthen concentrated under reduced pressure. The residual oil obtained isdiluted with 30 ml of benzene, and the solution is then depositeddirectly onto a silica gel column. The expected product is eluted withchloroform. After concentration of the chloroform phases, the solid iscrystallized once from cyclohexane and then from a hexane/benzenemixture. The white crystals of dibutyl9,10-dihydro-1,8,9-trihydrox-9,10-anthracene-α,β-endomaleate thusisolated melt at 148° C.

Analysis: C₂₆ H₂₈ O₇. Calc: C: 69.01; H: 6.24; O: 24.75. Found: C:68.86; H: 6.26; O: 24.85.

(2) A solution of 2 g of dibutyl9,10-dihydro-1,8,9-trihydroxy-9,10-anthracene-α,β-endomaleate in 7 ml offreshly distilled ortho-dichlorobenzene is brought at the boiling pointof ortho-dichlorobenzene for 24 hours, the solution being maintained inan inert atmosphere and protected from light.

After cooling, the mixture is diluted with hexane and the unreactedstarting material precipitates. After filtration, the filtrate isconcentrated under reduced pressure and the solution obtained isdeposited on a silica gel column. The expected product is eluted withbenzene. After concentration of the benzene phase, a yellow solid isobtained with a melting point of 56° C.

Analysis: C₂₆ H₂₈ O₇. Calc: C: 69.01; H: 6.24; O: 24.75. Found: C:68.96; H: 6.19; O: 24.48.

EXAMPLE 6 Dicyclohexyl 10-(1,8-dihydroxy-9-anthrone)-yl maleate (No. 11)

(1) To a suspension of 11.3 g of anthralin in 150 ml of anhydroustetrahydrofuran, protected from atmospheric moisture and light andplaced under an inert atmosphere, there are added 20.38 g ofdicyclohexyl acetylenedicarboxylate and 3.5 ml of a 0.5% methanolicsolution of lithium methylate. The reaction mixture is maintained at theboiling point of tetrahydrofuran for one hour. After concentration underreduced pressure, the product obtained is dissolved in a minimum oftoluene and deposited on a silica gel chromatography column. Thedicyclohexyl9,10-dihydro-1,8,9-trihydroxy-9,10-anthracene-α,β-endomaleate is elutedwith a 4:1 mixture of toluene/ethyl acetate, then crystallized from amixture of toluene and hexane and finally washed with methylenechloride. After drying, there are thus obtained 16 g of white crystalswith a melting point of 230° C.

Analysis: C₃₀ H₃₂ O₇. Calc: C: 71.41; H: 6.39. Found: C: 71.63; H: 6.48.

(2) A solution of 1.8 g of the above product in 7 ml ofortho-dichlorobenzene is maintained for 12 hours in an inert atmosphereand protected from light at the boiling temperature of the solvent.After cooling the solution is diluted with 100 ml of cyclohexane.

A portion of the starting material precipitates and is filtered off.

The filtrate is then concentrated and deposited on a silica gel column.The product is eluted with benzene. After evaporation of the benzenephases, a yellow solid is obtained having a melting point of 178° C.

Analysis: C₃₀ H₃₂ O₇. Calc: C: 71.41; H: 6.39. Found: C: 71.54; H: 6.42.

EXAMPLE 7 Dibenzyl 10-(1,8-dihydroxy-9-anthrone)-yl maleate (No. 12)

A suspension of 2.1 g of anthralin in 4 ml of benzylacetylenedicarboxylate is brought to a temperature of 140° C. in aninert atmosphere, then maintained for one hour at 120° C. after additionof several crystals of potassium carbonate. After cooling, the reactionmixture is dissolved in a minimum of chloroform and the chloroform phaseis deposited on a silica gel column.

The product is eluted with benzene; after concentration of the eluates,a yellow solid is obtained having a melting point of 84° C.

Analysis: C₃₂ H₂₄ O₇. Calc: C: 73.84; H: 4.65; O: 21.51. Found: C:73.67; H: 4.68; O: 21.41.

EXAMPLE 8 Methyl 3-[(1,8-dihydroxy-9-anthron)10-ylidene]-propionate (No.27)

To a solution of anthralin (5 g) in 300 ml of chloroform under an argonatmosphere and protected from light, 4 ml of methyl propiolate and 300mg of 4-dimethylaminopyridine are added under stirring in one batch.

The solution is then maintained at reflux for 20 hours. After coolingand washing with acidified water, the chloroform phase is decanted,dried over sodium sulfate and then concentrated. The residue is taken upin the minimum amount of benzene and the benzene phase is deposited on asilica gel column. The expected product is eluted with chloroform. Afterconcentration of the eluates, the solid obtained is recrystalized fromacetone. After drying under reduced pressure the yellow crystals have amelting point 172° C.

Analysis: C₁₈ H₁₄ O₅. Calc: C: 69.67; H: 4.55; O: 25.78. Found: C:69.60; H: 4.62; O: 25.83.

EXAMPLE 9 Ethyl 3-[(1,8-dihydroxy-9-anthron)10-ylidene]-propionate (No.28)

To a stirred solution of anthralin (5 g) in 300 ml of chloroform underan atmosphere of argon and protected from light, 3 ml of ethylpropriolate and 200 mg of 4-dimethylaminopyridine are added in onebatch.

The mixture is maintained for 36 hours at reflux. After cooling, themixture is washed with acidified water. The chloroform phase isdecanted, dried over sodium sulfate and then evaporated under reducedpressure. The residue is dissolved in the minimum amount of toluene andthe toluene phase is deposited on a silica gel column. The expectedproduct is eluted with toluene. The solid obtained after concentrationof the eluates is recrystalized from acetone. The yellow crystals thusisolated have a melting point of 145° C. after drying.

Analysis: C₁₉ H₁₆ O₅. Calc: C: 70.36; H: 4.97; O: 24.66. Found: C:70.45; H: 4.99; O: 24.62.

EXAMPLE 10 Pentyl 3-[(1,8-dihydroxy-9-anthron)10-ylidene]-propionate(No. 31)

A solution of 1 g of methyl(1,8-dihydroxy-9-anthron-10-ylidene)-3-propionate obtained, according toExample 8, in 25 ml of pentanol containing 2 drops of concentratedsulfuric acid is maintained at a temperature of 130° C. for one hour inan inert atmosphere and protected from light. The mixture is thenconcentrated under reduced pressure, the residue is taken up in tolueneand the toluene phases are washed with water, dried over sodium sulfateand finally deposited on a silica gel column. The product is then elutedwith methylene chloride. After concentration of the eluates 0.75 g of ayellow orange liquid is obtained.

Analysis: C₂₂ H₂₂ O₅. Calc: C: 72.12; H: 6.05; O: 21.83. Found: C:72.11; H: 6.09; O: 21.78.

EXAMPLE 11 Cyclohexyl 3-[(1,8-dihydroxy-9-anthron)10-ylidene]-propionate(No. 35)

A solution of 1 g of methyl3-[(1,8-dihydroxy-9-anthron)10-ylidene]-propionate, obtained accordingto Example 8, in 25 ml of cyclohexanol containing 2 drops ofconcentrated sulfic acid is maintained at a temperature of 130° for 5hours in an inert atmosphere and protected from light. The reactionmixture is then treated as in Example 9 above. After purification on asilica gel column, 0.7 g of the product is obtained which is thenrecrystalized from hexane. The yellow orange crystals are filtered anddried under reduced pressure. Melting point: 70° C.

Analysis: C₂₃ H₂₂ O₅. Calc: C: 73.00; H: 5.86; O: 21.14. Found: C:72.92; H: 5.89; O: 21.06.

EXAMPLE 12 Dimethyl 3-[(1,8-dihydroxy-9-anthron)10-ylidene]-succinate(No. 37)

To a solution of anthralin (10 g) in 500 ml of chloroform under an inertatmosphere and protected from light, 6.5 ml of methylacetylenedicarboxylate and 200 mg of 4-dimethylaminopyridine are addedin one batch. The reaction mixture is then maintained for 4 hours atreflux. After cooling and washing with water, the chloroform phase isdried over sodium sulfate and then concentrated under reduced pressure.The residue obtained is dissolved in a minimum of benzene and thebenzene phase is deposited on a silica gel column.

The expected product is eluted with chloroform. After concentration ofthe eluates, the solid obtained is recrystalized from a mixture ofbenzene and ethanol. The yellow crystals are filtered and dried underreduced pressure. Melting point: 152° C.

Analysis: C₂₀ H₁₆ O₇. Calc: C: 65.22; H: 4.38; O: 30.41. Found: C:65.15; H: 4.40; O: 30.31.

Regarding the treatment of psoriasis, a composition containing an activecompound of the present invention is applied topically to the affectedarea of the skin. Generally, the compositions are applied in a thickenedform with the aid of a thickening agent such as petrolatum U.S.P.

Examples of anti-psoriasis composition embodied within the scope of thepresent invention are as follows:

    ______________________________________                                        (1)   dicyclohexyl 10-(1,8-dihydroxy-9-                                                                      2      g                                             anthrone)-yl maleate                                                          Petrolatum U.S.P.        98     g                                       (2)   dibenzyl 10-(1,8-dihydroxy-9-                                                                          2      g                                             anthrone)-yl maleate                                                          Hydrocortisone           1      g                                             Petrolatum U.S.P.        97     g                                       (3)   pentyl 3-[(1,8-dihydroxy-9-anthron)-10-                                                                2      g                                             ylidene]-propionate                                                           salicylic acid           2      g                                             Petrolatum U.S.P.        96     g                                       (4)   methyl 3-[(1,8-dihydroxy-9-anthron)-10-                                                                0.5    g                                             ylidene]-propionate                                                           salicylic acid           2      g                                             Petrolatum U.S.P.        97.5   g                                       (5)   dimethyl 3-[(1,8-dihydroxy-9-anthron)-10-                                                              1      g                                             ylidene]-succinate                                                            Hard paraffin            5      g                                             Starch                   50     g                                             Soft white paraffin      44     g                                       ______________________________________                                    

As regards examples 1-4 above, the active compound is added toPetrolatum under stirring at 60° C. and, if desired, the salicylic acidor the hydrocortisone. After cooling at room temperature, the resultingsuspension is refined by passing it to roller mill.

By applying the above compositions once daily during three weeks,excellent results are obtained on the psoriasis areas of the skin. Theefficiency is superior or equal to compositions containing anthralin butwith no primary irritation and without staining of the skin.

What is claimed is:
 1. A composition to be topically applied to theskin, which contains in a paraffin vehicle suitable for application tothe skin, 0.01 to 5% by weight of a compound of the following formula:##STR8## wherein R₁ represents hydrogen or CO₂ R'₂,R₂ and R'₂, identicalor different, represent hydrogen, linear or branched chain alkyl radicalof 1 to 6 carbon atoms, cycloalkyl of 4 to 6 carbon atoms or benzyl, orR₁ and R₂ taken together form a --CO--, and n is 0 or 1,and mixturesthereof.
 2. A composition to be topically applied to the skin, whichcontains in a vehicle suitable for application to the skin, 0.01 to 5%by weight of a compound of the formula: ##STR9## wherein: R₂ representshydrogen, linear or branched alkyl of 1 to 6 carbon atoms, cycloalkyl of4 to 6 carbon atoms or benzyl, andn is 0 or 1,and mixtures thereof.
 3. Amethod for the treatment of psoriasis or acne which comprises topicallyapplying to the affected area of the skin an effective amount of thecomposition of claim
 2. 4. A method for treatment of psoriasis or acnewhich comprises topically applying to the affected area of the skin aneffective amount of the compound of the formula: ##STR10## wherein R₁represents hydrogen or CO₂ R'₂,R₂ and R'₂, identical or different,represent hydrogen, linear or branched chain alkyl radical of 1 to 6carbon atoms, cycloalkyl of 4 to 6 carbon atoms or benzyl, or R₁ and R₂taken together form a --CO--, and n is 0 or 1,and mixtures thereof.